Group B streptococcus (GBS) is currently the leading single cause of neonatal sepsis and the third most frequent cause of bacterial meningitis in the United States. Importantly, 50% of children surviving meningitis suffer from long term neurodevelopmental sequelae. Furthermore, GBS is of growing importance as cause of invasive bacterial disease in patients with diabetes. In the outgoing funding period we have defined three principle inflammatory patterns in GBS that essentially contribute to mortality in a neonatal sepsis model. First, we have identified lipoproteins as endotoxins that constitute functional equivalents to the well defined lipopolysaccharide in Gram-negative bacteria. Lipoproteins induce inflammatory cytokines through interaction with the Toll-like-receptors (TLR) 2 and 6. TLR2 furthermore mediates apoptosis of microglia and neurons in response to GBS which likely contributes to the substantial neurological sequelae of GBS meningitis. Second, we have uncovered a GBS cell bound, yet-to-be defined factor that induces cytokine formation in dependence on particle uptake and expression of the TLR-adapter protein MyD88, but cannot be assigned to established modes of TLR recognition. Finally, live GBS engage a TLR- and MyD88- independent pathway that results in the formation of IFN-p. The overall goal of this proposal is to better define the interphase between GBS and phagocytes with respect to GBS recognition and subsequent regulation of the inflammatory response in order to prepare adjunctive therapeutic strategies that target GBS substructures and host cell molecules. Specifically we intend to identify the MyD88-dependent GBS cell wall factor on the molecular level and dissect its most potent effect on the host cell transcription machinery. Next, we plan to define the roles of GBS phagocytosis (or invasion) and modification of GBS inside phagocytes for the inflammatory phenotype. Furthermore, we seek to determine the role of an aerobic metabolism in GBS that is turned on when GBS gets in contact to blood for lipoprotein formation and plan to define the contribution of individual lipoproteins to sepsis pathogenesis in vivo. Finally we will analyze the nature of interaction between lipoproteins and TLRs and intend to determine, whether and how lipoproteins exert potent apoptotic activity on CNS cells like microglia. The data generated by this study should help to better understand why a common colonizer turns into a sepsis pathogen in individual patients. The completion of these studies will allow us to understand how Group B streptococcus, the most common cause of severe bacterial infections in newborn infants, is recognized by the immune system. We believe this will eventually lead to better therapies against this devastating microbe.